title: Antitumor activity mediated by CpG: the route of administration is critical.
abstract: Unmethylated CpG oligodeoxynucleotides (CpG) are synthetic toll-like receptor 9 agonists that activate innate immune cells and which have been tested as an immune therapy in a number of cancer clinical trials. Although some antitumor immune responses have been reported, so far the majority of studies have failed to show significant clinical responses to CpG. Here we showed that the route of administration is critical to the antitumor activity of CpG. Although intravenous (i.v.) injection of CpG was capable of inducing the activation and expansion of tumor antigen-specific T cells, most of these activated T cells failed to migrate to tumor sites. By contrast, intratumoral (i.t.) injection of CpG led to extensive tumor infiltration of antigen-specific T cells and subsequent tumor suppression. We further showed that very high levels of inflammatory chemokines [regulated upon activation, normal T-cell expressed, and secreted (RANTES), interferon-inducible protein-10 (IP-10), monocyte chemoattractant protein-1, monocyte chemotactic protein (MCP5), macrophage inflammatory proteins (MIP1α, and MIP1β)] were induced in the tumor microenvironment after i.t. CpG injection, compared with administration by the i.v. route. It is interesting to note that, in vivo depletion of plasmacytoid dendritic cells greatly reduced the levels of chemokines induced; also, T-cell accumulation and antitumor effect were impaired. We also showed that i.t. but not i.v. CpG injection induced a broad antigen-specific T-cell response against tumor-derived antigens. Collectively, our data provides evidence that the route of CpG administration is a critical factor in mediating antitumor activity. By inducing localized inflammatory signals at tumor sites, i.t. CpG effectively promotes the migration, activation and function of immune cells, ultimately leading to improved tumor control.
authors.affiliation: Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Lou
authors.forename: Chengwen
authors.initials: C
authors.lastname: Liu
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizée
authors.forename: Weiyi
authors.initials: W
authors.lastname: Peng
authors.forename: Chunyu
authors.initials: C
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.forename: Brian A
authors.initials: BA
authors.lastname: Rabinovich
authors.forename: Yared
authors.initials: Y
authors.lastname: Hailemichael
authors.forename: Alexander
authors.initials: A
authors.lastname: Gelbard
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhou
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018946:Chemokine CCL5 / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004333:Drug Administration Routes; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D018945:Monocyte Chemoattractant Proteins / Q000276:immunology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000138:chemical synthesis; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9